PROJECT SUMMARY/ABSTRACT Data spanning over three decades show that hypothyroidism is highly prevalent in the chronic kidney disease (CKD) population, affecting 25% of those receiving dialysis therapy. In the general population hypothyroidism, defined by elevated thyrotropin (TSH) levels, has been associated with cardiovascular (CV) morbidity and mortality and impaired health-related quality of life (HRQOL), but until recently there was a paucity of data regarding its prognostic implications in CKD. Our pioneering studies supported by the PI?s NIH F32, K23, and R03 awards have advanced the field by showing that elevated thyrotropin (TSH) levels even within the ?normal? range (>3.0mIU/L) are associated with heightened risk of CV disease (e.g., coronary artery calcification, endothelial dysfunction) and death across multiple dialysis cohorts. With support of an American Thyroid Association grant, our research was also the first to show a link between high-normal TSH levels and worse HRQOL Short Form 36 scores in dialysis patients, particularly among subscales centered on physical health (e.g., physical function, energy/fatigue). However, there remains considerable controversy as to 1) whether thyroid dysfunction is causally associated with adverse patient-centered and CV outcomes, and 2) if elevated TSH levels represent thyroid functional disease vs. non-thyroidal illness in CKD. Moreover, as United States Renal Data System analyses show that levothyroxine (L-T4) is one of the most commonly prescribed medications in end-stage renal disease patients, there is pressing urgency for a randomized controlled trial (RCT) that will determine the efficacy and safety of L-T4 in this population. In the spirit of our recent discoveries and supportive findings by others, we propose this R01 study in which an Early-Stage Investigator, complemented by a uniquely well-qualified multi-disciplinary team of experts, will conduct a rigorously-designed and feasible randomized, double-blind, parallel two-arm trial of L-T4 vs. placebo among 336 hemodialysis patients with high-normal or subclinical hypothyroid TSH levels (>3.0-5.0 and >5.0-10.0mIU/L, respectively). Our primary objective will be to determine the effects of six months of L-T4 on the co-primary outcomes of HRQOL (Aim 1) and coronary artery calcification (Aim 2). Our main secondary objectives will be to determine the effects of L-T4 on the domains of physical performance (Aim 1), vascular health (Aim 2), and body composition (Aim 3). In a subcohort of 108 HD patients from the parent trial, we will also examine the effects of L-T4 on three novel exploratory secondary endpoints of muscle strength, cardiac function, and resting energy expenditure that will inform the framework of future multi-center corollary RCT?s. Successful completion of this R01 proposal will address major knowledge gaps by determining whether thyroid dysfunction is a novel, modifiable risk factor for impaired HRQOL and CV disease in CKD; defining the causal implications of thyroid dysfunction in CKD; establishing the efficacy and safety of L-T4 in this population; and generating a repository of data through a secondary substudy that will inform future trials of L-T4 in CKD.